Acquired or common varied immunodeficiency (CVI) is a heterogeneous collection of diseases characterized by low levels of immunoglobulins (Igs) and specific antibodies, especially IgG and IgA, but having percentages of B lymphocytes in blood ranging from low to greater than normal. Deficiencies in the capacity of CVI cells to secrete Ig, assayed in vitro [Wu, L., et al. (1973) J. Clin. Invest. 52, 3180-3189; Geha, R.S., et al., (1974) N. Engl. J. Med. 291, 1-6; de La Concha, E.G., et al., (1977) Clin. Exp. Immunol. 27, 208-215; Schwartz, S., et al., (1977) J. Clin. Invest. 59, 1176-1187; Siegal, F.P., et al. (1978) N. Engl. J. Med. 299, 172-178], and the variable-to-low numbers of plasmacytes in lymphoid tissues (Siegal, F.P., et al, (1977) Clin. Heamatol. 6, 355-422) demonstrate a profound defect inB-cell maturation in this disease. One or more defects in B cells are considered to be the primary cause of the disease in many cases of CVI (Wu, L, et al. Supra, de 1a Concha, E.G., et al. Supra, Siegal, F.P., et al. (1978) Supra). T-cell functions are also abnormal in 50-60% of patients (de la Concha, E.G., et al. Supra; Waldmann, T.A., et al., (1978) Ann. Intern. Med. 88, 226-238; World Health Organization (1979) Clin. Immunol. Immunopathol. 13, 296-359). High levels of suppressor T cells (de la Concha, E.G. et al., Supra; Siegal, F.P., (1978) Supra; Cunningham-Rundles, S., et al. (1981) J. Clin. Immunol. 1, 65-72) or suppressor monocytes (Siegal, F.P., et al. (1978) Supra) have been found in an occasional CVI patient, shown by inhibition of immune responses of normal donor cells in cocultures. However, replacement of suppressor T-cell populations with normal allogeneic T cells usually does not prevent the deficiency of patient B cells in in vitro assays.
Pokeweed mitogen (PWM) stimulation has been a standard assay to assess the functional capacity of B cells in peripheral blood to secrete Ig, although it is T cell dependent in its action (Wu, L., et al., Supra; Geha, R.S., et al. Supra; de la Concha, E.G., et al. Supra; Schwartz, S., et al. Supra; Siegal, F.P., et al. (1978) Supra; Siegal, F.P., et al. (1977) Supra; Cunningham-Rundles, S., et al. Supra). We have described improved conditions for induction of B-cell differentiation using PWM and B-cell mitogen Staphylococcus aureus strain Cowan I (herein called Cowan I) (Saiki, 0., et al, (1981) J. Immunol. 127, 1044-1047). High numbers of Ig-secreting cells are obtained in cultures of all normal donors tested, even if they are low responders to either mitogen alone or have excess levels of T-cell suppression (Saiki, 0, et al. (1982) Cell Immunol., in press). Cowan I is a T-cell independent mitogen for B cells (Fosgren, A., et al. (1976) Eur. J. Immunol. 6, 207-212; Schuurman, K.R.B., et al. (1980) J. Immunol. 125, 820-824), and proliferative responses to this agent have been studied in CVI. Schuurman, et al. (Schuurman, K.R.B., et al., Supra) found a correlation of Cowan I-induced DNA synthesis and the presence of B cells in the blood of 11 cases of severe combined immunodeficiency, agammaglobulinemia, or CVI. We have described goat F(ab').sub.2 fragment antibodies to IgM and IgD that also are T-cell independent mitogens for B cells (Saiki, 0., et al. (1982) Clin. Immunol. Immunopathol., in press). The purpose of the present invention is to show that differences in B-cell proliferation, and differences in Ig secretion by stimulatory means in CVI determines B-cell subsets or stages of differentiation. These subsets of CVl will then serve as diagnostic and therapeutic tools. This is an unexpected result from the use of B-cell mitogens, and such B-cell mitogens in varying combinations. Therefore, it will be obvious to those skilled in the art to use such mitogens in combinations other than those illustrated below. The invention therefore is not limited to the combinations shown, these are for illustrative purposes. Other mitogen combinations may serve as well.